Anti-LPS antibody for Pediatric Nonalcoholic Fatty Liver Disease

抗 LPS 抗体治疗小儿非酒精性脂肪肝

• 批准号: 9335406
• 负责人: MIRIAM B. VOS
• 金额: $ 19.5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335406
• 关键词: Address; Adult; Adverse effects; Affect; Age; Alcoholic Hepatitis; Antibodies; Australia; Biopsy; Blood; Canada; Caring; Cattle; Child; Child health care; Childhood; Chronic; Clinic; Clinical; Clinical Research; Clinical Trials; Colostrum; Controlled Clinical Trials; Data; Decision Making; Double-Blind Method; Effectiveness; Endotoxemia; Enrollment; Enzymes; Escherichia coli; Exposure to; FDA approved; Feces; Future; Genes; Goals; Health; Healthcare; Hepatic; Histology; Immunoglobulin G; Individual; Inflammation; Inflammatory disease of the intestine; Innate Immune Response; Insulin Resistance; Letters; Life Style; Lipids; Lipopolysaccharides; Liver; Measurement; Medical; Milk; Mission; Monitor; Mucous Membrane; Multicenter Trials; National Institute of Child Health and Human Development; Obesity; Participant; Patients; Permeability; Placebo Control; Placebos; Population; Positioning Attribute; Powder dose form; Quality of life; Randomized; Recruitment Activity; Regulatory T-Lymphocyte; Research Personnel; Resolution; Ribosomal RNA; Risk; Role; Safety; Sample Size; Subgroup; System; Target Populations; Testing; Therapeutic; Traveler' s diarrhea; United States; United States National Institutes of Health; Universities; Vaccinated; blood lipid; chronic liver disease; cytokine; design; gut microbiome; improved; insulin sensitivity; liver inflammation; liver transplantation; medical food; member; metabolomics; microbial; microbiome; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel therapeutics; pathogenic bacteria; phase 1 study; phase 2 study; phase III trial; pregnant; prevent; primary outcome; response; secondary outcome; standard of care; transcriptomics; treatment strategy; treatment trial

Project Summary Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that affects 10-30% of children in the United States. NAFLD is surprisingly aggressive in children and there is currently no approved therapy for it. Because the onset of NAFLD is often in young children (8-12 years), any potential therapeutic for NAFLD will need to be almost risk-free. In this proposal, we seek to study IMM-124E, a medical product that was initially developed for traveler’s diarrhea and has been available over the counter in Australia for years. IMM-124E is a hyperimmune bovine colostrum manufactured by drying the cow’s first milk and packaging it into caplets. This hyperimmune “milk powder” is enriched with IgG against E. coli bacterial products (LPS) by vaccinating the pregnant cow. Because altered microbiome, increased gut permeability, and increased LPS have been shown to be important in the mechanism of NAFLD, IMM-124E has logical support for efficacy in NAFLD. Phase I studies in adults have shown improved insulin resistance, liver enzymes, and promotion of regulatory T-cells. This proposal is designed to test IMM-124E in a small phase II study in children with NAFLD in order to assess preliminary efficacy and safety endpoints and to improve understanding of the mechanisms. This will be accomplished through two aims in a 12 week double-blind, randomized, placebo-controlled clinical trial in children with NAFLD. Aim 1 will determine if 3 months of treatment with IMM-124E in combination with lifestyle changes (standard of care (SOC)) results in greater improvement in 1) hepatic lipid and inflammation, 2) insulin sensitivity, 3) blood lipids, in children with NAFLD, compared to placebo with SOC as well as monitor safety related endpoints. Aim 2 will define mechanisms of action-related endpoints including: stool microbiome, metabolomics, LPS and transcriptomics of innate immune response genes and correlate these with changes in clinical measurements. The proposal leverages state-of-the art platforms at Emory University including high throughput, high resolution metabolomics and established centers for microbiome and transcriptomics to accomplish the mechanism studies. Additionally, we have the clinical population to quickly enroll children into this trial. This proposal addresses the mission of the NIH NCCIH and NICHD by rigorously investigating a complementary treatment with the potential to improve health for large numbers of children. If successful, these studies would support designing a future large scale phase III trial. These studies will enhance our understanding of the role of the gut in pediatric NAFLD and if positive, will result in a low risk, low side effect, high yield therapeutic for pediatric NAFLD.

项目摘要 非酒精性脂肪性肝病(NAFLD)是一种慢性肝病，影响着美国10%-30%的儿童 各州。NAFLD在儿童中的侵略性令人惊讶，目前还没有批准的治疗方法。因为 NAFLD的发病通常发生在幼儿(8-12岁)，任何可能的NAFLD治疗方法都需要 几乎没有风险。在这个提案中，我们试图研究IMM-124E，这是一种最初开发的医疗产品 用于旅行者腹泻，多年来一直在澳大利亚的柜台出售。IMM-124E是一种 高免疫力的牛初乳，通过将奶牛的第一批奶烘干并包装成小块制成。这 高免疫力的“奶粉”富含针对大肠杆菌细菌制品(LPS)的免疫球蛋白。 怀孕的母牛。因为微生物群的改变，肠道通透性的增加，以及内毒素的增加已经被证明 IMM-124E在NAFLD的发病机制中具有重要作用，对NAFLD的疗效有逻辑支持。第一阶段研究 成年人的胰岛素抵抗、肝酶和调节性T细胞的促进都得到了改善。这 该提案旨在对患有非酒精性脂肪肝的儿童进行一项小型第二阶段研究中测试IMM-124E，以评估 初步疗效和安全终点，并提高对机制的理解。这将是 在12周的双盲、随机、安慰剂对照的临床试验中，通过两个目标实现 患有非酒精性脂肪肝的儿童。目标1将确定3个月的IMM-124E联合 生活方式的改变(护理标准(SOC))导致1)肝脏脂质和炎症的更大改善， 2)NAFLD儿童的胰岛素敏感性，3)血脂，与服用SOC和监测仪的安慰剂进行比较 与安全相关的终端。目标2将定义与作用相关的终点的机制，包括：粪便微生物组， 代谢组学、内毒素和先天免疫反应基因的转录组学，并与这些变化相关 临床测量。该提案利用了埃默里大学最先进的平台，包括High 生产能力、高分辨率代谢组学和建立的微生物组和转录组中心 完成机理研究。此外，我们有临床人口可以迅速将儿童纳入 这场审判。这项提案通过严格调查一项 补充治疗，有可能改善大量儿童的健康。如果成功，这些 研究将支持设计未来的大规模第三阶段试验。这些研究将增进我们对 肠道在儿童NAFLD中的作用，如果呈阳性，将导致低风险、低副作用、高产量 治疗儿童非酒精性脂肪肝。